Original Article Adverse Events Due to Suspected Hypersensitivity in Patients with Essure Micro-Inserts Robert K. Zurawin, MD*, and Jonathan L. Zurawin From the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas (both authors).

ABSTRACT Study Objective: To review reported adverse events associated with suspected nickel hypersensitivity and subsequent clinical outcomes in patients with Essure implants and to evaluate the correlation of nickel –related adverse events with positive results of nickel patch testing. Design: Case series (Canadian Task Force classification II-3). Measurements and Main Results: Reports of suspected nickel hypersensitivity reported from 2001 through July 21, 2010, were collected from de-identified data obtained from the MAUDE (Manufacturer and User Facility Device Experience) da- tabase and reports to the manufacturer directly from treating physicians, and published results for the 650 patients in the Phase II and Pivotal trials. Clinical outcomes and symptom resolution, when available, were obtained from de-identified information provided by the treating physicians to the manufacturer. Patients were not directly contacted for the study, and patient files were not reviewed. Patch testing was performed at the discretion of the treating physicians. Results were reported as positive or negative, without mention of the method or brand of patch testing used. Conclusion: Even considering the possibility of underreporting by several orders of magnitude, the reported incidence of ad- verse events suspected to be related to nickel hypersensitivity in patients with Essure micro-inserts is extremely small (0.01%). The incidence of confirmed nickel reactions is even smaller. This very low incidence of clinical reactions is consis- tent with data from other nickel-containing implantable devices and is reassuring, raising the question of whether nickel re- actions are clinically relevant in the use of nitinol-containing micro-inserts for hysteroscopic sterilization. Journal of Minimally Invasive Gynecology (2011) 18, 475–482 Ó 2011 AAGL. All rights reserved. Keywords: Allergy/allergic; Hives; ; Nickel; ; Sensitive/sensitivity

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Nickel is currently the most common contact allergen in cade. The most recent data from the North American Contact the industrialized world and is a leading cause of contact Group, who patch tested approximately 25, 626 dermatitis, especially in female individuals [1]. In the United male and female patients from 1992 to 2004, showed a steady States, the rate of nickel allergy has increased in the past de- increase in nickel sensitivity, from 14.5% in 1992 to 18.8% in 2004. Further, they showed that women demonstrated The authors have no commercial, proprietary, or financial interest in the a consistently higher percentage of nickel sensitivity than products or companies described in this article. men. From 1992 to 2004, the positivity rate in women ranged Dr. Zurawin is a consultant for Conceptus, Inc. from 18% to 24% [2]. If there were concordance between Presented as an abstract at the 2009 AAGL Global Congress, Orlando, this reported positivity to nickel patch testing and clinical Florida, November 17, 2009. Corresponding author: Robert K. Zurawin, MD, Department of Obstetrics reactions to a nitinol-containing micro-insert, with more and Gynecology, Baylor College of Medicine, 6620 Main St, Ste 1450, than 400 000 Essure devices implanted, the expected number Houston, TX 77030-2305. of patients exhibiting nickel sensitivity would range from E-mail: [email protected] approximately 72 000 to 96 000. However, this was not Submitted January 9, 2011. Accepted for publication April 30, 2011. observed. To explain this vast discrepancy, a thorough Available at www.sciencedirect.com and www.jmig.org review of the physiologic effects of the use of nickel alloys

1553-4650/$ - see front matter Ó 2011 AAGL. All rights reserved. doi:10.1016/j.jmig.2011.04.009 476 Journal of Minimally Invasive Gynecology, Vol 18, No 4, July/August 2011 in medical devices is presented so that the practicing gyne- reports revealed a lack of correlation between suspected nickel cologist may benefit from the research and experience of allergy and reported adverse events. A summary of the 63 re- colleagues in other medical specialties who have dealt ports of suspected nickel hypersensitivity is shown in Fig. 1. with reactions to analogous devices. Positive Results Materials and Methods Micro-Inserts Removed and Symptoms Resolved Reports of suspected nickel hypersensitivity reported from 2001 through July 21, 2010, were identified from In 9 of the 13 patients who tested positive on the patch adverse events reported to Conceptus Inc (Mountain View, test, the micro-device was removed. Symptoms resolved in CA), de-identified data were obtained from the MAUDE 4 of the 9 patients. Of these 4 patients, 1 experienced symp- (Manufacturer and User Facility Device Experience) data- toms of rash and itching, and another experienced increased base, and the results for 650 patients in the Phase II and asthma. In these 2 patients, the treating physician judged the Pivotal trials were obtained from reports to the manufacturer symptoms to be directly related to the micro-inserts. In the directly from treating physicians and the published results of other 2 patients, it remains unclear whether the symptoms the Phase II and Pivotal trials. Clinical outcomes and symp- were related to the micro-inserts because of their unusual na- tom resolution, when available, were obtained from de- ture; 1 patient experienced swelling in 1 leg after the proce- identified information provided by the treating physicians dure. She underwent patch testing, and was found to be to the manufacturer. Patients were not directly contacted positive for nickel allergy. The devices were removed, and for this study, and patient files were not reviewed. Patch test- the leg swelling resolved within a month. The other patient ing was performed at the discretion of the treating physician. reported nausea for several months after the procedure. Re- Results were reported as positive or negative without men- sults of a nickel allergy test were positive. The devices were tion of the method or brand of patch testing used. removed laparoscopically via bilateral salpingectomy, and the nausea reportedly resolved soon thereafter. Results Micro-Inserts Removed and Symptoms Unresolved Sixty-three reports of suspected nickel hypersensitivity were identified. Of 20 patients who underwent patch testing, Two patients who tested positive for nickel allergy did not 13 tested positive and 7 tested negative. Review of these experience symptom resolution after micro-insert removal.

Fig. 1 Reports of suspected nickel hypersensitivity. LTFU 5 lost to follow-up; NA 5 data not available. Zurawin and Zurawin. Essure and Nickel Hypersensitivity 477

One of the 2 demonstrated symptoms of arthritis and pelvic attempts to collect additional data, no follow-up information pain more than 2 years after Essure implantation. At laparo- was provided. scopy, 1 of the devices was observed to have perforated the fallopian tube, and the contralateral device had perforated Micro-Inserts Not Removed the uterus and was lodged in the myometrium. The devices were removed, with improvement of pain but persistence In 2 patients in whom nickel allergy was not suspected of arthritis. The other patient experienced rash and hives before the procedure, the micro-inserts were placed, and 4 years after Essure placement. Allergy testing was positive the patients developed symptoms. Patch testing yielded pos- for nickel. Although she experienced no symptoms for itive results; however, the Essure devices were not removed. 4 years after placement until the recent episode, the devices One patient experienced a rash after Essure placement, which were removed; however, the symptoms did not resolve. In was treated with methylprednisolone. The rash was ‘‘nearly both cases, the treating physician judged the symptoms to resolved’’ at 3-month follow-up hysterosalpingography, be unrelated to the nickel in the micro-inserts. after which time the patient was lost to follow-up. She was able to rely on Essure for contraception, and the possi- Micro-Inserts Removed and Symptom Resolution ble relationship to nickel allergy remains uncertain. The Unknown other patient underwent placement of the micro-inserts, and after several weeks, a skin test was positive for nickel In 2 patients the devices were removed; however, no ad- allergy. She claimed to have developed a skin reaction as ditional information could be gathered to assess resolution of a result of the Essure devices, and requested that the de- symptoms. One patient experienced nausea, shivering, and vices be removed. She was treated with diphenhydramine. pain after placement of the Essure devices, which was per- The treating physician judged that the symptoms were not formed at the same time as removal of etonogestrel implants. related to the micro-inserts but planned to remove them Nine months later, the patient underwent laparoscopic bilat- anyway. Of note, a third patient with positive results of eral salpingectomy because of persistent intermittent 1-sided a nickel allergy test remained asymptomatic. This patient pain in the iliac region. Pathologic analysis was unremark- underwent testing before the Essure procedure, and notified able. Symptom resolution is unknown because the patient her physician of symptoms the day after the procedure. was lost to follow-up. In another case, reported anonymously A detailed description of findings in patients with positive via MedWatch, Essure was placed in a patient with a known patch test results is given in Table 1. nickel allergy. No symptoms were reported. The device was removed at the patient’s request. Relationship to nickel Negative Patch Test Results remains unknown; however, in the absence of any symp- toms, it cannot be determined whether any reaction to nickel Of 7 patients with negative patch test results, 5 experi- occurred. enced rash, hives, or itching; 1 experienced tingling and swollen lips; and 1 experienced pain at 2 years after Essure Micro-Inserts Removed Despite Symptom Improvement placement. None of these symptoms in the 7 patients were deemed related to the micro-inserts. In 2 patients, the One patient underwent micro-insert removal despite im- micro-inserts were removed. One patient underwent a com- provement of symptoms. She initially reported pain 1 day plete hysterectomy because of medical reasons unrelated to after Essure placement, and underwent diagnostic laparos- the Essure devices, and symptoms resolved despite negative copy, which revealed no abnormalities. On the evening of results of a patch test. The patient who experienced itching the laparoscopy, the patient experienced increased pain, after Essure placement subsequently underwent hysterec- hives, and rash. She was treated with diphenhydramine, tomy and salpingectomy, after which the symptoms re- and the symptoms improved. Despite improvement, the solved. The 5 patients who did not undergo micro-insert physician removed the micro-devices via laparoscopic cor- removal were treated conservatively with antihistamines or nual resection and bilateral salpingectomy. The pathologist steroids. identified leukocytes and eosinophils within the specimen, A detailed description of findings in patients with nega- and postoperative skin testing revealed nickel allergy. tive patch test results is given in Table 2. Because the symptoms had resolved by the time the devices were removed, it could not be determined whether there was Discussion a true hypersensitivity reaction of clinical significance. Implants in a wide range of medical applications are com- Micro-Insert Removal Planned But No Further posed of alloys that contain nickel. Thus, the mechanism that Information Provided creates the potential for adverse reactions to implants that contain metals in practical applications is worth noting [3]. One patient with a confirmed nickel allergy experienced Metal ions are with a high immunogenic potential, 1 constant pain, which increased with menses. The physician with Ni2 representing the most common contact allergen was planning micro-insert removal; however, despite that primarily affects the skin. Common manifestations are 478 Table 1

Positive nickel allergy patch test results in 13 patients

Time from Patient/Incident procedure to identifier symptom onset Symptoms Intervention Treatment results Comment Micro-inserts removed; symptoms resolved (n 5 4) AR-07499-J73H Postprocedure Swelling of 1 leg Devices removed Symptom resolved Not known whether related to nickel AR08545-OXR9 6 Months Nausea Devices removed Symptom resolved Not known whether related to nickel AR-09946-HR3P Postprocedure Rash and itching Referred to dermatologist; Symptoms resolved Related to nickel allergy, devices removed per treating physician AR-13311-5Z8V 1 Year Increased symptoms of Referred to allergist; Symptoms resolved Related to nickel allergy, asthma devices removed per treating physician Micro-inserts removed; symptoms unresolved (n 5 2) AR-11220-SWVS 21 Years Arthritis, pelvic pain Devices removed Symptoms unresolved Not related to nickel allergy, per treating physician AR-15158-BYXK 4 Years Rash and hives Devices removed Rash unresolved Not related to nickel allergy, per treating physician Micro-inserts removed; not known whether symptoms resolved (n 5 2) AR-04054-VLB3 Postprocedure Nausea, shivering, Devices removed Not known Not known whether related

discomfort sometimes to nickel 2011 July/August 4, No 18, Vol Gynecology, Invasive Minimally of Journal associated with iliac pain on right side AR-05122-OFDG %5 Days Not known Devices removed Not known Not known whether related to nickel Micro-inserts removed despite symptom improvement (n 5 1) AR-05145-XK32 1 Day Pain, rash, hives Diphenhydramine; devices Symptoms improved Not known whether related removed to nickel Micro-inserts removed; no further information provided (n 5 1) AR061341 Not known Constant pain increasing Device removal planned Not known Not known whether related with menses to nickel Micro-inserts not removed (n 5 3) AR04668 1–3 Days Rash Methylprednisolone and Rash nearly resolved at Not known whether related steroids 3-month follow-up to nickel hysterosalpingography AR-08745-6NRD 1 Month Skin reaction Oral medication Not known Not related to nickel allergy, per treating physician AR050597 Not applicable No symptoms None Not applicable Patient had confirmed nickel allergy but no symptoms Zurawin and Zurawin. Essure and Nickel Hypersensitivity 479

Table 2

Negative nickel allergy patch test results in 7 patients

Time from procedure to Patient/Incident identifier symptom onset Symptoms Intervention Treatment results Micro-inserts removed; symptoms resolved (n 5 2) AR-08870-L3N3 Postprocedure Total body itching Devices removed Symptom resolved AR-09555-VNL1 1–2 Months Generalized overall itching Antihistamines; devices Symptom resolved removed Micro-inserts not removed (n 5 5) AR03469 4 Weeks Rash and hives Prednisone and Symptoms resolved diphenhydramine AR050911 3 Weeks Rash No information available Not known AR-07620-84R4 2 Weeks Tingling, swollen lips Prednisone Not known AR-08018-FKR2 1 Day Hives, itching Referred to dermatologist Not known AR-15044-HZ3L 2 Years Pain Referred to allergist and Not known specialist contact hypersensitivity with hand eczema, generalized responses, diagnostic tests in patients with symptoms of dermatitis, and urticaria [3]. Transition metals such as nickel dermatitis include open patch, closed patch, lymphocyte have an ionic radius too small to be antigenic but can act as transformation, and macrophage migration inhibition tests. a (a low-molecular-weight determinant group that of Patients with eczema can be tested using oral provocation itself is nonimmunogenic but becomes so when placed on [1]. On the skin, contact urticants go through the epidermis a larger molecule) when its partially filled d-shell oxidizes and react with preformed specific IgE molecules, causing to an electropositive cation, enabling interaction with tissue the subsequent release of histamine and other cell-bound protein. There is increasing evidence that the actual immu- mediators of inflammation. Consequently, immediate-type nogenic form of nickel is the trivalent ion, Ni31, rather hypersensitivity to nickel can be diagnosed in vitro using than the traditional Ni21 [1]. the radioallergosorbent test, which uses radiolabeled anti- How does nickel become a clinically relevant allergen? It IgE to recognize the IgE in a patient’s serum. is not triggered by dietary intake. The mean oral intake of In vivo, reaction to the skin-prick test for immediate-type nickel from the diet per person is estimated to be 150 to allergy is visible on the patient’s skin [1]. 900 mg/day [4]. In a meta-analysis of systemic contact der- Approximately 80% of patients with positive patch test matitis after nickel introduced orally into the body, it was es- results have a clinical history of metal sensitivity [7]. timated that 1% of patients allergic to nickel would develop However, patch testing is not always a reliable predictor of a systemic reaction to a normal diet of nickel, and that 10% a systemic nickel allergic reaction. A large percentage of would react to nickel intake levels of 0.55 to 0.89 mg [5]. In- the population that tests positive on the nickel sulfate skin- sofar as toxicity, not allergenicity, the maximum recommen- patch test remains asymptomatic and exhibits no noticeable ded tolerable amount of nickel administered in a human signs of nickel allergic hypersensitivity. Conversely, many being via intravenous fluids is 0.5 mg/kg/day, or approxi- who report sensitivity actually test negative on skin patch mately 7 mg/kg in an adult weighing 70 kg [6]. testing. The validity of self-reported nickel allergy is low, Nickel allergic is generally character- and tends to overestimate the true prevalence of nickel ized by delayed-type hypersensitivity. After sensitization allergy. Josefson et al [9] observed that fewer than 60% of via contact, a reaction can develop from even minor contact patients who self-report allergy to nickel were actually 1 with Ni 2 -containing metals. Reactions associated with im- positive when patch tested. A commercially available lym- plants are typically type IV hypersensitivity cell-mediated phocyte transformation test (Orthopedic Analysis, LLC, reactions that occur via skin contact and elicit lymphocyte Chicago, IL) has recently been developed, with claims to ac- T-cell action. The microenvironment of the lymphocytes in- curately predict allergic reactions to nickel-containing alloys volved determines the variation in tissue-related allergic used in implant surgery. However, the company’s own dis- reactions [7]. claimer states that issues of sensitivity and specificity remain Patch testing is the standard for diagnosis of nickel allergic unresolved, as well as how implant performance is related to contact dermatitis, and most commonly entails placing 2.5% positive reactivity results [10]. or 5% concentrated nickel sulfate in petrolatum on the The concern about hypersensitivity and adverse reactions skin for 48 hours. The skin is examined 72 to 96 hours later to the nickel content of implantable devices with regard to for a local reaction [8]. For delayed-type hypersensitivity ion release or leaching is of critical importance. Nickel (type IV) that generally characterizes nickel allergic alloys that commonly come in contact with the skin must 480 Journal of Minimally Invasive Gynecology, Vol 18, No 4, July/August 2011

Table 3

Material composition of components of Essure micro-insert

Component Material Composition Outer coil Chromium-doped nitinol (nickel-titanium) 55% Nickel, 44% titanium, trace chromium Inner coil, thread coil 316L Stainless steel w62.5% Iron, 17.6% chromium, 14.5% nickel Stopper band, platinum band, platinum ring, bump Platinum-iridium 90% Platinum, 10% iridium Solder Tin-silver 95% Tin, 5% silver Fiber PET polyester, white R92% Polyester, ,5% titanium dioxide, ,3% fiber lubricants be differentiated from biological nickel-containing alloys, cardiac defects that uses nitinol. An in vitro study in which 1 and the physiologic reactions are qualitatively distinct. the release of Ni2 was measured after immersion in physio- Nitinol is an alloy composed of a mixture of nickel and tita- logic Hank’s solution demonstrated a titanium oxide coating nium, with the proportion varying with each implantable de- that forms and is later covered by a calcium-phosphate vice. It is commonly used in surgical implants such as layer. In vivo, endothelialization of the surface of the Am- orthopedic staples, vena cava filters, dental devices, and platzer device is complete in 3 months [3]. Analysis of the intravascular stents because of its unique shape-memory Ni21 release of Amplatzer occluders revealed 3-fold in- and good biocompatibility [5]. Because cardiac devices are creased serum levels (1.50 ng/mL) from baseline (0.47 ng/ exposed to the bloodstream, they should be most likely to mL) at 1 month after implantation, which returned to preim- release detectable blood levels of metal ions and initiate plantation levels at 12 months [12]. a hypersensitivity reaction [3]. In fact, hypersensitivity reac- Coronary artery in-stent restenosis has been associated tions to the materials used in endovascular devices represent with nickel allergy in some studies, whereas others have only uncommon reactions that may lead to local or systemic not been able to confirm such an association [13]. One study complications subsequent to implantation [7]. Worldwide found that 10% of individuals with significant in-stent reste- each year, more than 1.5 million percutaneous coronary nosis at 6 months had positive adverse reactions to nickel or revascularization procedures are performed, most involving molybdenum in patch tests despite all having negative patch- intracoronary stent implantation. Intracoronary stents made test results for 316L stainless steel [14]. Another study found of 316L stainless steel contain approximately 12% nickel in that only repeat in-stent restenosis was associated with pos- addition to other potentially sensitizing metals such as chro- itive metal patch test results, whereas other smaller studies mium and molybdenum. These metals may be eluted by have not confirmed an association [10]. surrounding blood and body fluids [10]. Nitinol-associated Rigatelli et al [15] reported placing a nitinol-containing nickel allergy cases are rare, with a risk factor of approxi- atrial shunt in 9 patients with proved nickel allergy. Eight mately 1 in 17 000 heart and endovascular devices. This of the 9 patients developed chest discomfort, exertional may be explained in part because in physiologic solution, dyspnea and asthenia, and mild leukocytosis, which was nitinol forms a titanium oxide coating along with a surface described as a ‘‘device syndrome.’’ After 1 week of therapy layer of calcium phosphate that is thought to minimize with prednisone and clopidogrel, the symptoms completely leaching and protect against nickel hypersensitivity [11]. resolved [15]. The authors concluded that nickel allergy is Results from an in vitro study measured the nickel release not itself a contraindication to use of a nitinol device to close from nitinol (NiTi), CoCrNi, and NiCr alloys common in atrial septal defects and that adverse effects are mild and vascular stents suggest that metal ion release from the stud- manageable with low-dose prednisone and antiplatelet ther- ied alloys was insufficient to activate expression of cellular apy. It remain unclear whether in-stent restenosis or compli- adhesion molecules on endothelial surfaces or to stimulate cations associated with septal occluders are consequences of cytotoxicity. Although nitinol had the highest concentration nickel or other metal allergy or of some other as-yet unde- of nickel in the studied alloys, it had the lowest nickel ion re- tected cause [7,10]. lease [7]. This may help explain the low observed rate of hy- Documented cases related to nickel sensitivity and metal persensitivity reactions. joint replacement failure are rare. However, eczematous re- The use of nickel-containing devices for closing cardiac actions have been reported. One study found that the risk of defects has been exceptionally well tolerated, with more surgical revision in total hip arthroplasty procedures was not than 50 000 devices placed worldwide. The rate of nickel- increased in patients with metal allergy [16]. In addition, related adverse events associated with these devices is ex- Schram et al [11] noted that the connection of nickel allergy ceedingly low when taking into account the aforementioned and failure of metal orthopedic implants and cardiac devices observed prevalence of dermal sensitivity [3]. is not clear, citing the existing, mainly retrospective, publi- The Amplatzer septal occluder (AGA Medical Corp, cations that suggest only an association of nickel allergy Golden Valley, MN) is one such device used for closing with implant failure rather than determine causation. Zurawin and Zurawin. Essure and Nickel Hypersensitivity 481

Patients who are metal-allergic can tolerate orthopedic pros- suggest that the follicular and ovulatory phases of the theses that contain the metals to which they are allergic [7]. cycle have a considerable inhibitory role on delayed In orthodontics, nickel is regularly used without compli- hypersensitivity-type reactions and that negative responses cations. In orthodontic wires, nitinol has corrosive properties to patch tests performed during these phases could be similar to those of stainless steel [17], and preorthodontic false-negative [20]. Patch testing may, therefore, be con- testing for metal allergy is not routinely performed. founded by the phase of a woman’s cycle. Although dermatitis at or proximal to the site of dental and The Essure micro-insert is placed during the early prolif- orthodontic endoprostheses has been noted in the literature, erative phase of the menstrual cycle, during which time the reactions to prostheses consisting of medical-grade stainless immune response is least pronounced. If there were to be any steel alone are rare [5]. There is also evidence that immuno- immunologic reaction, it would be blunted, only to emerge tolerance has a role. Dental braces containing high amounts again during the late secretory phase just before menstrua- of nickel alloys (e.g., chromium with 60%–80% nitinol) tion. This may explain a delayed response to placement resulted in nickel tolerance in girls who subsequently had noted in several reports of adverse events, although it is dif- their ears pierced compared with high nickel sensitivity in ficult to differentiate these symptoms from those caused by girls who had their ears pierced but who did not previously occult perforation of the devices or other inflammatory or in- wear such dental braces. This tolerance may be caused by fectious process. The incidence of these events is statisti- a mechanism involving low nickel exposure orally over cally too small to reach clinical relevance. time [18]. Review of the medical literature confirms that there are By weight, the nitinol alloy used to form the outer coil of no reliable tests to predict nickel hypersensitivity caused by the Essure micro-insert is composed of about 55.8% nickel, implantable devices. It has yet to be determined whether 44% titanium, and 0.25% chromium, which is comparable to adverse reactions to metal-containing implants result the composition of nitinol in other surgically implanted de- from a specific cellular immune response, and confirmation vices. The nickel ions in nitinol alloys are tightly bound to of a type IV hypersensitivity reaction would necessitate bi- titanium. Conceptus Corp, the manufacturer of the Essure opsy of the affected tissue showing effector T cells and micro-inserts, uses a chromium-doped nickel-titanium alloy macrophages. Currently, there is inadequate evidence to that is processed so that the entire alloy surface is covered support such an association; thus, the relationship between with a protective layer of titanium oxide, which acts to min- systemic reaction and cutaneous allergy is unknown. imize nickel ion release. The material composition of the Nickel allergy determined using patch testing should, components of the Essure micro-insert are given in Table 3. therefore, not be an absolute contraindication to the use A corrosion study analyzed the amount of nickel leached of biomaterials that contain nickel [3]. The incidence of ad- into solution after the Essure micro-insert was placed in sa- verse reactions to implantable nickel alloys is negligible line solution for varying amounts of time and compared that across all known reported devices, and because self- with the average amount of natural nickel ingested daily reported reaction to nickel remains an unreliable indicator from food and water (300 mg/day). The study found that of nickel hypersensitivity, a history of a reaction to cutane- the highest measured leaching rate of nickel was 0.14 mg/ ous exposure to nickel does not necessarily indicate contra- day, which is approximately 2143 times less than the average indication to use of devices containing nickel-titanium human daily intake from food and water [19]. alloy. It has been shown that nickel-sensitive individuals The cyclicity of the hormones of the menstrual cycle may may be safely observed or treated with prednisone, antihis- also have a role in the effects observed during insertion of tamines, or antiplatelet agents, without having to remove Essure micro-inserts and may regulate expression of nickel the device [7,15]. hypersensitivity in women. Bonamonte et al [20] noted Like all of the aforementioned devices, the incidence of that dermatologic contact irritation seems to be more preva- reported nickel-related reactions or complications from the lent during the premenstrual secretory phase, as noted by Essure micro-insert remains far below the range of 18% to a more intense response to patch tests with sodium lauryl 24% in women with contact nickel allergy. Of the 436 937 sulfate, compared with the follicular phase of the cycle, Essure kits sold since its commercial release, there have which is when the Essure device is traditionally placed. been only 63 reported cases in which nickel hypersensitivity During the follicular phase, a temporary protective role in was suspected, or 0.014%, and none in clinical trials. It is inhibiting the eliciting phase of allergic contact dermatitis safe to assume that these 63 cases represent underreporting is observed. In the days before menstruation, contact derma- of suspected nickel allergy cases. Even if the reporting of ad- titis intensifies [21]. Noting how estradiol induces inhibition verse effects were to be underestimated by several orders of of delayed hypersensitivity-type reactions, their study fo- magnitude, the Essure data demonstrate an almost negligible cused on the possibility that ovulation could inhibit contact occurrence of proved nickel-related reactions. The findings sensitization mechanisms. Patch tests were performed dur- of a recent European analysis of 4000 Essure commercial ing the ovulatory and secretory phases and showed a signifi- procedures assessing all reported complications found cantly reduced response to the patch tests during the only 2 patients with previously undiagnosed nickel sensitiv- follicular and ovulatory phases. The authors’ findings ity who underwent laparoscopic salpingectomy, for an 482 Journal of Minimally Invasive Gynecology, Vol 18, No 4, July/August 2011 incidence of 0.05% [22]. Significantly, devices were placed References in 25 patients with known nickel allergy, without adverse ef- 1. Hostynek JJ. Sensitization to nickel: etiology, epidemiology, immune fects. This further substantiates the lack of correlation be- reactions, prevention, and therapy. Rev Environ Health. 2006;21: tween suspected symptoms and nickel allergy in women 253–280. with Essure micro-inserts and corroborates the findings in 2. Rietschel RL, Fowler JF, Warshaw EM, et al. Detection of nickel sen- the present study as evidenced by the 1 patient with a con- sitivity has increased in North American patch-test patients. Dermatitis. firmed positive nickel patch test who was completely asymp- 2008;19:16–19. 3. Anselmino M, Ribezzo M, Orzan F. Nickel allergy: how deep? Acta tomatic. Cardiol. 2009;64:104–106. 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